Mycolic acid synthesis enzymes

Mycolic acid synthesis enzymes are a group of essential proteins involved in the biosynthesis of the unique, long-chain fatty acids that form the primary structural component of the mycobacterial cell wall. This pathway, predominantly the Fatty Acid Synthase II (FAS-II) system, includes key enzymes such as Enoyl-ACP reductase (InhA), Beta-ketoacyl-ACP synthase (KasA), and 3-ketoacyl-ACP reductase (MabA) (Nature Reviews Microbiology, 2005). These enzymes are critical for the survival and virulence of Mycobacterium tuberculosis, as the mycolic acid layer provides a formidable permeability barrier against antibiotics and host immune responses (PubMed, 2019). Therapeutic agents like Isoniazid and Ethionamide target this pathway by inhibiting InhA, leading to the loss of acid-fastness and eventual cell lysis (StatPearls, 2023). Because the FAS-II system is absent in humans, these enzymes are highly attractive targets for selective antitubercular drug development (Chemical Reviews, 2011). Ongoing research also focuses on later-stage enzymes like Polyketide synthase 13 (Pks13) and the Antigen 85 complex to overcome emerging multi-drug resistance (Journal of Medicinal Chemistry, 2020). Disruption of this pathway is a cornerstone of modern tuberculosis treatment, though its efficacy is often challenged by the development of genetic resistance in the target enzymes (WHO, 2021).

Other names

Mycolic acid biosynthesis pathwayFatty acid synthase II systemFAS-II enzymesMycobacterial cell wall synthesis enzymesInhA complex

Drugs targeting these enzymes primarily act by inhibiting the elongation of fatty acids in the Fatty Acid Synthase II (FAS-II) pathway. For example, Isoniazid and Ethionamide are prodrugs that, once activated by KatG or EthA respectively, form adducts with NAD or NADP to inhibit InhA (enoyl-ACP reductase), thereby blocking the synthesis of long-chain mycolic acids (StatPearls, 2023; PubChem, CID 3750). Other agents like Delamanid and Pretomanid inhibit the synthesis of methoxy-mycolic and keto-mycolic acids, disrupting the mycobacterial cell wall (WHO, 2022). Newer inhibitors target the condensation steps mediated by KasA or the final assembly steps mediated by Pks13 (Journal of Medicinal Chemistry, 2020).